Methylene-disalicylic acid derivative



Patented Jan. 14, 1930 UNITED STATES PATENT OFFICE SAMUEL LEWIS SUMMERS, F FORT WAS HING'ION, PENNSYLVANIA.

METHYLENE-DISALIOYLIC ACID DERIVATIVE No Drawing.

My products may be prepared as follows Starting with methylene-disalicylic acid the first main step is the conversion of this 1 acid into an ester, preferably its diethyl ester. As the alcohol is replaced in the second step the nature of the alcohol used is of little sential product is the diethyl ester of methylene-disalicylic acid:

oermomcoocim (4.3 on? ouawro600can (423') This is freed from sulphuric acid by Wash (nitrobenzyl) substitution product with 400 ing with water.

The second main step is to convert this ester into the corresponding amide. One method of accomplishing this is as follows:

348 pounds of the above described ester is mixed with 200 pounds of strong aqueous ammonia (concentrated or 28%) and heated in an autoclave for 8 hours at 110 C. The excess of ammonia, the water and the alcohol formed during the reaction are gotten rid of by evaporation, which leaves methylene-disalicyl amide as the essential product:

,cnsnmmooms It is immaterial whether this amide is obtained in this way through the ester or from methylene-disalicylic acid by some other method. I

The third main step is to substitute nitro- Application filed Octber 12, 192;. Serial No. 312,201;

benzyl grou s in thetwo hydroxyls of the above descri ed amide. One way ofdoing this, .to which I do not limit myself, is as follows: u

286 pounds of methylene-disalicyl amide is intimately mixed with 345 pounds of nitrobenzyl chloride and 250 pounds of sodium carbonate, and heated to 130 C. for 24 hours. The essential product is a di(nitrobenzyl) ether of methylene-disalicyl amide: o

CalidOCHzCqHrNOQCONHz on? This is purified by washing with water. In this preparation any one of the three isomeric" 5 nitrobenzyl chlorides may be usedwithrorresponding differences in the products, which, however, are of the same .nature and go through the subsequent reactions in the same way to yield products which are similar and which are equally useful for pharmaceutical purposes;

The fourth main step is to reduce the two 1 nitrobenzyl groups of the above described product to aminogroups. This may be effected by the use of various reducing agents; but' one way is as follows: Mix 556 pounds of the abovedescribed dipounds of free metallic zinc, preferably in the form of dust, and 1800 pounds of hydrochloric acid. After the heatof the spontaneous chemical reaction has subsided, the mass is heated to C. and maintained at that temperature for 4 hours. The mixture is made slightly alkaline by the addition of ammonia water, which'c'auses the separation of the desired diamino derivative, which is filtered off and washed with water to free it from zinc salts. The product is dissolved in alcohol and freed from any remaining zinc salts by saturating the solution with hydrogen sulphide. The alcohol is eliminated by evaporation, leaving the essential product which is a di(aminobenzyl) ether of methylene-disalicyl amide:

' o.r[, ooH,cH4NH,)ooNH,

orn

otHawommmNneooNm The fifth main step is the acetylation of the NH, groups in this compound; it bein possible to mtroduce two or four ace groups accordin to the proportions of reactants used an the time and temperature of heating. One way of accomplishing this acetylation, to which I do not limit myself, is to heat 496 pounds of the amino derivative (obtained as above) with pounds of glacial acetic acid to the temperature of 110 (3., for 24 hours. The product is washed with water to eliminate excess of acetic acid. The essential product is the diacetyl derivative of a. di(aminobenzyl) ether of methylene-disalicyl amide:

mmoomommnooongoonm @(OOH CdLNHCOOHdOONH:

By the use of larger proportions of acetic acid, or preferably acetanilide, acetyl groups may be introduced into the -two other "NI-I groups. The diacetyl and the tetraacet 1 derivatives are crystalline substances inso uble in water but soluble in alcohol. Both of them are useful as antiseptics, antineuralgic antiarthritic and antlrheumatic drugs; 0 which the doses may be 90 to grains per day.

Having thus described my invention, 1 claim:

1. The hereindescribed di(a'minobenql) ethers of methylene-disalicyl amide, typi ed by the formula wherein B may represent the acetyl group or hydrolien.

2. e hereindescribed acetylation products of the di (aminobenzyl) ethers of meth lene-disalicyl amide, typified b the formul .moomommooxvnn .moomommoom wherein B may represent the acetyl up or hydrogen, but having at least tw as as acetyl groups.

In testimony whereof, I have hereunto signed m name at Ambler, Pennsylvania, this 9th a of October, 1928.

S L LEWIS SUMMERS. 

